Direct synthesis of the beta-l-rhamnopyranosides.

Article abstract of DOI:10.1021/ol0340890

The direct formation of beta-l-rhamnopyranosides by means of thioglycoside donors protected with a 2-O-sulfonate ester and, ideally, a 4-O-benzoyl ester, is reported. Activation is achieved with the combination of 1-benzenesulfinyl piperidine and triflic anhydride in the presence of 2,4,6-tri-tert-butylpyrimidine. Selectivities vary from moderate to good, and the sulfonyl group is easily removed post-glycosylation with sodium amalgam in 2-propanol.

Full text of DOI:10.1021/ol0340890

ORGANIC
LETTERS
2003
Vol. 5, No. 5
781-784
Direct Synthesis of the
â-L-Rhamnopyranosides
David Crich* and John Picione
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received January 19, 2003
ABSTRACT
The direct formation of â-L-rhamnopyranosides by means of thioglycoside donors protected with a 2-O-sulfonate ester and, ideally, a 4-O-
benzoyl ester, is reported. Activation is achieved with the combination of 1-benzenesulfinyl piperidine and triflic anhydride in the presence of
2,4,6-tri-tert-butylpyrimidine. Selectivities vary from moderate to good, and the sulfonyl group is easily removed post-glycosylation with sodium
amalgam in 2-propanol.
The chemical synthesis of the â-L-rhamnopyranosides is a
cognate problem to that of the â-D-mannopyranosides1
insofar as both are cis-equatorial type glycopyranosidic bonds
for which, until recently, there has been no viable direct
approach other than the use of 2,3-O-carbonate-2 or 2,3-O-
alkylidene-protected3 glycosyl bromides in conjunction with
insoluble silver-based promoters. Closer inspection, however,
reveals the rhamnoside problem to be the more complex of
the two. First, our recent solution to the â-mannoside problem
involving torsionally disarmed, 4,6-O-benzylidene-protected
donors, thioglycosides,4 or glycosyl sulfoxides5 and triflate
counterions cannot be applied in the rhamnose series because
of the 6-deoxy function. Second, the 6-deoxy system
influences any equilibrium between covalently bound donors
and contact and solvent separated ion pairs and therefore
impinges directly on the glycosylation mechanism. We
describe here a direct entry to the â-L-rhamnosides by means
2-O-sulfonyl-protected rhamnosyl thioglycosides, activated
with the combination of 1-benzenesulfinyl piperidine (BSP)6,7
and triflic anhydride.
Embarking on this project, we took our cue from the work
of Schuerch in which it was demonstrated that the 2-O-
sulfonyl group is capable of stabilizing R-mannosyl and
R-rhamnosyl sulfonate esters and of directing glycosylation,
albeit with a very limited range of acceptors, to the
â-position.8,9,10 Preliminary investigations soon revealed the
instability of trans-diaxial 2-O-sulfonyl-R-glycosyl thiogly-
cosides and directed our attention to the â-thiorhamnosides
as donors. A number of 2-O-sulfonates were prepared as
outlined in Scheme 1 and were screened for their ability to
promote the â-glycosylation of 3â-cholestanol as set out in
(1) (a) Pozsgay, V. In Carbohydrates in Chemistry and Biology; Ernst,
B., Hart, G. W., Sinay¨, P., Eds.; Wiley-VCH: Weinheim, 2000; Vol. 1, p
319. (b) Gridley, J. J.; Osborn, H. M. I. J. Chem. Soc., Perkin Trans. 1
2000, 1471. (c) Barresi, F.; Hindsgaul, O. In Modern Methods in
Carbohydrate Synthesis; Khan, S. H., O’Neill, R. A., Eds.; Harwood:
Amsterdam, 1996; p 251.
(2) Backinovsky, L. V.; Balan, N. F.; Shashkov, A. S.; Kochetkov, N.
K. Carbohydr. Res. 1980, 84, 225.
(3) Iversen, T.; Bundle, D. R. Carbohydr. Res. 1980, 84, C13.
(4) (a) Crich, D.; de la Mora, M.; Cruz, R. Tetrahedron 2002, 58, 35.
(b) Crich, D.; Smith, M. J. Am. Chem. Soc. 2002, 124, 8867. Crich, D.; Li,
H. J. Org. Chem. 2002, 67, 4640.
(6) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015.
(7) BSP and TTBP are available from www.lakeviewsynthesis.com.
(8) (a) Srivastava, V. K.; Schuerch, C. J. Org. Chem. 1981, 46, 1121.
(b) Awad; L. F.; El Ashry, E. S. H.; Schuerch, C. Bull. Chem. Soc. Jpn.
1986, 59, 1587.
(9) Reviewed in: Crich, D. In Glycochemistry: Principles, Synthesis,
and Applications; Wang, P. G., Bertozzi, C. R., Eds; Dekker: New York,
2001; p 53. Crich, D. J. Carbohydr. Chem. 2002, 21, 663.
(10) During the later stages of this investigation an isolated example of
â-mannosylation with a 2-O-sulfonate protected trichloroacetimidate donor
was described: Abdel-Rahman, A. A.-H.; Jonke, S.; El Ashry, E. S. H.;
Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 2002, 41, 2972.
(5) (a) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321. (b) Crich, D.; Li,
H.; Yao, Q.; Wink, D. W.; Sommer, R. D.; Rheingold, A. L. J. Am. Chem.
Soc. 2001, 123, 5826. (c) Crich, D.; Dudkin, V. J. Am. Chem. Soc. 2002,
124, 2263.
10.1021/ol0340890 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/07/2003

an even more strongly disarmed system. Mindful of the need
for maximum orthogonality of protection in any donor, we
elected to introduce a carboxylate ester, rather than a further
sulfonate group, to fulfill this function. It having been
previously shown that 3-O-benzoyl groups are strongly
R-directing in mannosylation by the glycosyl triflate method,13
presumably through neighboring group participation, the only
option was a 4-O-carboxylate ester. Toward this end,
regioselective 3-O-monobenzylation of R-thiorhamnoside 3
was conveniently achieved through treament with dibutyltin
oxide and then benzyl bromide. Sulfonylation then afforded
19, benzoylation of which gave the requisite donor 21
(Scheme 2). Unfortunately, the highly crystalline nature of
Scheme 1. Screening of Sulfonates for Propensity to
â-Rhamnoside Formationa
Scheme 2. Preparation of Donors 21 and 22a
a Key: (a) PhSH, NaH, HMPA, 78%; (b) NaOMe (cat.), MeOH,
95%; (c) PTSA (cat.), 2,2-dimethoxypropane, acetone, 79%; (d)
BnBr, NaH, THF, 87%; (e) MeOH/H2O, AcOH, reflux, 90%; (f)
(i) Bu2SnO, benzene, (ii) BnBr, CsF, DMF, 71%; (g) Et3N, RSO2Cl,
CH2Cl2, 60-89%; (h) (i) BSP, Tf2O, TTBP, -60 °C, CH2Cl2, (ii)
cholestanol/CH2Cl2.
Table 1. All couplings were carried out by a standard protocol
involving activation of a mixture of glycosyl donor, BSP,
a Key: (a) (i) Bu2SnO, benzene, (ii) BnBr, CsF, DMF, 71%; (b)
RSO2Cl, Ag2O, KI, sym-collidine, CH2,Cl2, 19: 55%, 20: 52%;
(c) Et3N, BzCl, CH2Cl2, 21: 90%, 22: 88%.
Table 1. â-Rhamnosylation of 3â-Cholestanol with Donors
8-12
this substance, and of the corresponding acetate, rendered it
all but insoluble in dichloromethane at -60 °C and, so, of
no use as a glycosyl donor in our system. This problem was
circumvented through preparation of the o-trifluoromethyl
analogue 22, which proved much more pliable, via 20
(Scheme 2).
A series of glycosylations were then conducted with 22
as donor (Scheme 3) under the standard conditions with the
results reported in Table 2. Comparison of the last entry of
donor
SO2R
product (% yield)
â/R ratio
8
9
10
11
12
p-C6H4Br
p-C6H4F
p-C6H4CN
p-C6H4CF3
CH2CF3
13 (74)
14 (81)
15 (69)
16 (75)
17 (70)
2:1
2:1
4:1
5.5:1
4.4:1
and 2,4,6-tri-tert-butylpyrimidine (TTBP)7,11 in dichlo-
romethane at -60 °C with triflic anhydride followed by
addition of the acceptor alcohol. It is assumed, based on
extensive work in the mannose series, that the combination
of thioglycoside, BSP, and triflic anhydride results in the
rapid formation of a co-valent glycosyl triflate12 which is
the actual glycosyl donor.
Scheme 3. â-Rhamnosylation with Donor 22 and Subsequent
Desulfonylationa
The optimal combination of yield and selectivity was
obtained with the p-trifluoromethylbenzenesulfonate 11 but
it was apparent that even this highly disarmed donor was
unlikely to be sufficiently selective with less-reactive,
carbohydrate-based acceptors. We reasoned that a further
increase in â-selectivity could be obtained by the introduction
of a second electron-withdrawing protecting group, i.e., with
a Key: (a) (i) BSP, TTBP, Tf2O, CH2Cl2, (ii) ROH/CH2Cl2; (b)
Na/Hg, 2-propanol, THF.
(11) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323.
(12) Crich, D.; Sun, S. J. Am. Chem. Soc. 1997, 119, 11217.
782
Org. Lett., Vol. 5, No. 5, 2003

Table 2. â-Rhamnosylation with Donor 22 and Subsequent Desulfonylation
Table 1 with the first in Table 2, for which the only difference
is the exchange of a benzyl ether for a benzoate ester, reveals
a significant increase in selectivity with the more highly
disarmed system. In general, â-rhamnosylation with donor
22 proceeds well with primary and more-reactive secondary
acceptors. With the less reactive secondary acceptors the
stereoselectivity falls off reaching a minimum for the systems
studied for the difficult case of the glucose 4-OH acceptor.
It is noteworthy that, as in our â-mannosylations, tertiary
alcohols, represented here by 1-adamantanol, are extremely
â-selective.
Finally, attention was turned to removal of the sulfonyl
group. Among the many methods known for the removal of
sulfonate esters, simple treatment with sodium amalgam in
2-propanol was selected for reasons of ease of operation and
mildness of conditions. All the â-rhamnosides prepared from
donor 13 were thus exposed to this reagent (Scheme 3),
resulting in the isolation of the desulfonylated glycosides
30-36 which had also undergone removal of the benzoate
ester (Table 2).
(13) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291.
Org. Lett., Vol. 5, No. 5, 2003
783

Concerning the assignment of stereochemistry, differentia-
of which are necessarily less efficient. Further optimization
studies are in progress and will be reported in due course.
tion between the â- and R-2-O-sulfonyl protected rhamno-
1
sides was made on the basis of the JCH coupling at the
anomeric carbon14 with the former typically having a value
in the range 152.3-159.8 Hz and the latter 167.2-172.3 Hz.
Combined with the ability to form R-rhamnosides directly
and in high yield from donors 37 and 38, the present work
extends the scope of our standardized thioglycoside/sulfona-
mide/triflic anhydride coupling to one of the more difficult
classes of glycosidic bond. For all but the least reactive of
acceptors the methodology we describe compares favorably
with other approaches to â-rhamnosides involving either
indirect methods15 or intramoleclar aglycone delivery,16 both
Acknowledgment. We thank the NIH (GM 57335) for
support of this work.
Supporting Information Available: Synthetic details and
characterization for all new molecules. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) Bock, K.; Pedersen, C. J. Chem. Soc., Perkin Trans. 2 1974, 293.
(15) Lichtenthaler, F. W.; Metz, T. W. Tetrahedron Lett. 1997, 38, 5477.
(16) Lau, R.; Schu¨le, G.; Schwaneberg, U.; Ziegler, T. Liebigs 1995,
1745.
OL0340890
784
Org. Lett., Vol. 5, No. 5, 2003